Maureen M. Tedesco

Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation

Apelin is a potent inodilator with recently described antiatherogenic properties. We hypothesized that apelin might also attenuate abdominal aortic aneurysm (AAA) formation by limiting disease-related vascular wall inflammation. C57BL/6 mice implanted with osmotic pumps filled with apelin or saline were treated with pancreatic elastase to create infrarenal AAAs. Mice were euthanized for aortic PCR analysis or followed ultrasonographically and then euthanized for histological analysis. The cellular expression of inflammatory cytokines and chemokines in response to apelin was also assessed in cultured macrophages, smooth muscle cells, and fibroblasts. Apelin treatment resulted in diminished AAA formation, with a 47% reduction in maximal cross-sectional area (0.74 vs. 1.39 mm(2), P < 0.03) and a 57% reduction in macrophage infiltrate (113 vs. 261.3 cells/high-power field, P < 0.0001) relative to the saline-treated group. Apelin infusion was also associated with significantly reduced aortic macrophage colony-stimulating factor expression and decreased monocyte chemattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha mean mRNA levels. Apelin stimulation of cultured macrophages significantly reduced MCP-1 and TNF-alpha mRNA levels relative to baseline (2.03- and 1.89-fold reduction, P < 0.03, respectively) but did not affect intimal adhesion molecule expression or medial or adventitial cell cytokine production. Apelin significantly reduces aneurysm formation in the elastase model of human AAA disease. The mechanism appears to be decreased macrophage burden, perhaps related to an apelin-mediated decrease in proinflammatory cytokine and chemokine activation.

The Utility of Endovascular Simulation to Improve Technical Performance and Stimulate Continued Interest of Preclinical Medical Students in Vascular Surgery

OBJECTIVE New training paradigms in vascular surgery allow for early specialization out of medical school. Surgical simulation has emerged as an educational tool for trainees to practice procedures in a controlled environment allowing interested medical students to perform procedures without compromising patient safety. The purpose of this study is to assess the ability of a simulation-based curriculum to improve the technical performance and interest level of medical students in vascular surgery. DESIGN Prospective observational cohort study of medical student performance. SETTING Academic medical center. PARTICIPANTS Forty-one medical students (23 first year, 15 second year, 3 other) enrolled in a vascular surgery elective course. Students completed a survey of their interests and performed a renal stent procedure on an endovascular simulator (pretest). The curriculum consisted of didactic teaching and weekly mentored simulator sessions and concluded with a final renal stent procedure on the simulator (posttest). Objective procedural measures were determined during the pre- and posttest by the simulator, and subjective performance was graded by expert observers utilizing a structured global assessment scale. After the course, the students were surveyed as to their opinions about vascular surgery as a career option. Finally, 1 year after the course, all students were again surveyed to determine continued interest in vascular surgery. RESULTS The objective and subjective criteria measured on the simulator and structured global assessment scale significantly improved from pre- to posttest in terms of performer technical skill, patient safety measures, and structured global assessments. Before beginning the course, 8.5% of the students expressed high interest in vascular surgery, and after completing the course 70% were seriously considering vascular surgery as a career option (p = 0.0001). More than 95% of the students responded that endovascular simulation increased their knowledge and interest in vascular surgery. In the 1-year follow-up survey (n = 23 medical students), 35% had already entered their clinical years. Seventy percent of the students were still considering vascular surgery, while several other career options were still popular including the surgical subspecialties (70%), interventional cardiology (57%), and interventional radiology (48%). Most respondents indicated the major reasons for continued interest in vascular surgery were the ability to practice endovascular procedures on the simulator (100%) and mentorship from vascular surgery faculty (78%). CONCLUSIONS The use of high fidelity endovascular simulation within an introductory vascular surgery course improves medical student performance with respect to technical skill, patient safety parameters, and global performance assessment. Mentored exposure to endovascular procedures on the simulator positively impacts long term medical student attitudes towards vascular surgery. Simulator-based courses may have the potential to be an important component in the assessment and recruitment of medical students for future surgical training programs.

Analysis of In Situ and Ex Vivo Vascular Endothelial Growth Factor Receptor Expression During Experimental Aortic Aneurysm Progression

Objective—Mural inflammation and neovascularization are characteristic pathological features of abdominal aortic aneurysm (AAA) disease. Vascular endothelial growth factor receptor (VEGFR) expression may also mediate AAA growth and rupture. We examined VEGFR expression as a function of AAA disease progression in the Apolipoprotein E–deficient (Apo E−/−) murine AAA model. Methods and Results—Apo E−/− mice maintained on a high-fat diet underwent continuous infusion with angiotensin II at 1000 ng/kg/min (Ang II) or vehicle (Control) via subcutaneous osmotic pump. Serial transabdominal ultrasound measurements of abdominal aortic diameter were recorded (n=16 mice, 3 to 4 time points per mouse) for up to 28 days. Near-infrared receptor fluorescent (NIRF) imaging was performed on Ang II mice (n=9) and Controls (n=5) with scVEGF/Cy, a single-chain VEGF homo-dimer labeled with Cy5.5 fluorescent tracer (7 to 18 &mgr;g/mouse IV). NIRF with inactivated single chain VEGF/Cy tracer (scVEGF/In, 18 &mgr;g/mouse IV) was performed on 2 additional Ang II mice to control for nonreceptor-mediated tracer binding and uptake. After image acquisition and sacrifice, aortae were harvested for analysis. An additional AAA mouse cohort received either an oral angiogenesis inhibitor or suitable negative or positive controls to clarify the significance of angiogenesis in experimental aneurysm progression. Aneurysms developed in the suprarenal aortic segment of all Ang II mice. Significantly greater fluorescent signal was obtained from aneurysmal aorta as compared to remote, uninvolved aortic segments in Ang II scVEGF/Cy mice or AAA in scVEGF/In mice or suprarenal aortic segments in Control mice. Signal intensity increased in a diameter-dependent fashion in aneurysmal segments. Immunostaining confirmed mural VEGFR-2 expression in medial smooth muscle cells. Treatment with an angiogenesis inhibitor attenuated AAA formation while decreasing mural macrophage infiltration and CD-31+ cell density. Conclusion—Mural VEGFR expression, as determined by scVEGF/Cy fluorescent imaging and VEGFR-2 immunostaining, increases in experimental AAAs in a diameter-dependent fashion. Angiogenesis inhibition limits AAA progression. Clinical VEGFR expression imaging strategies, if feasible, may improve real-time monitoring of AAA disease progression and response to suppressive strategies.

Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE-/- model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

AAA disease: mechanism, stratification, and treatment.

Abstract:  Abdominal aortic aneurysm (AAA) is a common and frequently lethal disease of older Americans. No medical therapy has been proven effective in retarding progression of small AAAs prior to surgical repair. With the emerging ability of magnetic resonance (MR) flow imaging and MR‐based computational analysis to define aortic hemodynamic conditions, and bio‐imaging strategies to monitor aortic inflammation real time in vivo, the opportunity now exists to confirm the potential value of medical interventions such as supervised exercise training as first line therapy for small AAA disease.

Portal vein thrombosis following laparoscopic sleeve gastrectomy for morbid obesity.

A high index of suspicion is necessary to diagnose portal vein thrombosis following laparoscopic bariatric procedures.

Enhanced Abdominal Aortic Aneurysm Formation in Thrombin-Activatable Procarboxypeptidase B–Deficient Mice

Objective—To determine whether procarboxypeptidase B (pCPB)−/− mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. Methods and Results—Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN]). Apolipoprotein E−/−OPN−/− mice are protected from experimental AAA formation. Murine AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion. Increased mortality secondary to AAA rupture was observed in pCPB−/− mice at the standard PPE dose. At reduced doses of PPE, pCPB−/− mice developed larger AAAs than wild-type controls (1.01±0.27 versus 0.68±0.05 mm; P=0.02 [mean±SD]). C5−/− and OPN−/− mice were not protected against AAA development. Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in pCPB−/− mice. Conclusion—This study establishes the role of CPB in experimental AAA disease, indicating that CPB has a broad anti-inflammatory role in vivo. Enhanced AAA formation in the PPE model is the result of increased plasmin generation, not unregulated C5a- or OPN-mediated mural inflammation.

Risk Factors for Developing Postprocedural Microemboli following Carotid Interventions

PURPOSE To determine risk factors predictive of microemboli found on diffusion-weighted magnetic resonance imaging (DW-MRI) following carotid angioplasty and stenting (CAS) with distal protection and carotid endarterectomy (CEA). METHODS A retrospective review was conducted of all carotid interventions at a single institution between 2004 and 2006. In that time frame, 64 carotid interventions (34 CAS, 30 CEA) were performed in 63 male patients (mean age 69.5 years, range 52 to 91) with DW-MRI scans available for review. Patient characteristics, including age, gender, smoking history, diabetes mellitus, hypertension, hyperlipidemia, obesity (body mass index >30), coronary artery disease (CAD), chronic obstructive pulmonary disease, peripheral vascular disease, and atrial fibrillation, were documented. For the CAS patients, anatomical and procedural characteristics, including fluoroscopy time, contrast volume, performance of an arch angiogram, and lesion anatomy, were recorded. Bivariate analyses were performed to determine which parameters were associated with the occurrence of acute postprocedural microemboli found on DW-MRI by 2 blinded neuroradiologists. RESULTS Twenty-four (71%) of the 34 CAS patients and 1 (3%) of the 30 CEA patients demonstrated new cerebral microemboli postoperatively. In the bivariate analyses of all patient, anatomical, and procedural characteristics, only a history of CAD was associated with an increased risk of microemboli; 20 (80%) of the 25 patients who had postprocedure microemboli had CAD compared to 18 (46%) of 39 patients without microemboli (p=0.007). Twenty (53%) of the 38 (59%) patients with CAD developed microemboli compared to 5 (19%) of the 26 patients without CAD (p=0.007). All other patient, procedural, and anatomical characteristics were not found to be independent risk factors predictive of postprocedure microemboli. CONCLUSION CAS with distal protection carries a significantly greater risk for developing new microemboli compared to CEA. Of all the risk factors analyzed, only a history of CAD emerged as an independent risk factor for the development of microemboli following carotid intervention. This finding may influence the decision to perform CAS in patients deemed high risk solely due to the presence of CAD.

Reduction of postprocedure microemboli following retrospective quality assessment and practice improvement measures for carotid angioplasty and stenting

OBJECTIVE We have previously demonstrated a 70% incidence of microemboli on diffusion weighted magnetic resonance imaging (DW-MRI) following carotid angioplasty and stenting (CAS). The purpose of this study is to compare the incidence of microemboli in two distinct time periods when procedural modifications were implemented into a CAS program. METHODS Following a retrospective quality review of our CAS cohort (n = 27) from November 2004 through April 2006 (period 1), we enrolled patients (n = 20) from May 2006 through February 2008 (period 2) undergoing CAS into a prospective cohort that included obtaining pre- and postprocedure DW-MRI exams. Procedural modifications during period 2 included the preferential use of closed-cell systems (60% vs 0% in period 1), early heparinization at the initiation of arterial access, and elimination of an arch angiogram. The hospital records of these 47 patients were reviewed; symptoms, comorbidities, lesion characteristics, periprocedural information, and postoperative outcomes were collected. The incidence and location of acute, postprocedural microemboli were determined using DW-MRIs. RESULTS Twenty (74%) CAS patients from period 1 and seven (35%) patients from period 2 demonstrated acute microemboli on postprocedural DW-MRI (P = .02). The mean number of microemboli in period 1 was 4.1 +/- 5.3 vs 1.5 +/- 2.7 during period 2 (P = .04). Two of the 27 patients (7.4%) during period 1 experienced temporary neurologic changes that resolved within 36 hours. None of the patients during period 2 exhibited any neurologic changes. Patient demographics, comorbidities, and presenting symptoms were similar between the two groups except for smoking prevalence, female presence, and obesity (BMI > 30). Period 2 patients when compared with period 1 had more technically challenging anatomy with more calcified lesions (68% vs 27%), longer lesions (15.9 mm vs 8.2 mm), and higher incidence of ulceration (55% vs 27%) (all P < .04). CONCLUSION Despite successful performance of 47 consecutive CAS procedures without permanent neurologic sequelae, significant reductions in periprocedural embolic events as identified via DW-MRI lesions may be achieved through implementation of quality improvement measures identified through continuous outcome analysis. The long-term neurologic benefits associated with reduced subclinical neurologic events remains to be determined.

Hybrid Treatment of Celiac Artery Compression (Median Arcuate Ligament) Syndrome

A 53-year-old woman presented with severe, post-prandial generalized abdominal pain and a 50-pound unintentional weight loss over a 3-month period. There had been a prior chronic history of this discomfort, but it had never reached this level of severity and it had not been associated with weight loss. Over the previous 3 months, her symptoms worsened to the point that she could not tolerate anything beyond clear liquids. Her prior surgical history included three cesarean sections, a total abdominal hysterectomy, a laparoscopic cholecystectomy, laparoscopic lysis of adhesions on three separate occasions, and a rectocele repair. Her last operation was 11 years prior to this presentation. Her past medical history was significant for fibromyalgia, chronic fatigue syndrome, narcotic analgesic dependence, anxiety, and hyperlipidemia. She has smoked a half of a pack of cigarettes per day for the past 30 years. She denied any alcohol or illicit drug use and her family history was noncontributory. Upon physical examination, her weight was 116 pounds, down from a weight of 165 pounds 3 months prior. She exhibited temporal wasting. Her abdominal exam was notable for intermittent diffuse mild tenderness and a scaphoid abdomen. Auscultation revealed no abdominal bruit. She had normal peripheral pulses. Extensive gastrointestinal evaluation including colonoscopy, upper endoscopy, and small bowel follow-through radiography were all normal. A CT-angiogram to rule out mesenteric vascular compromise revealed compression of the celiac artery by the median arcuate ligament (MAL), post-stenotic dilation, and characteristic ‘‘fish-hook’’ appearance (Fig. 1). Duplex ultrasound confirmed 70% stenosis of the proximal celiac artery by two-dimensional compression, changing with breathing patterns, as well as elevated velocities of 360 cm/s in the proximal celiac orifice. Post-stenotic turbulence was also noted in the hepatic and splenic arteries. Based on the patient’s clinical and radiographic findings, the diagnosis of MAL syndrome was considered. We planned for a potential hybrid approach with part-laparoscopic and part-endovascular methods to relieve her obstruction. She was taken to the operating room for laparoscopic MAL release (Fig. 2). Significant scarring and fibers were carefully dissected off the celiac trunk and allowed full release/relaxation of the compressed celiac vessel. Postoperatively, her abdominal pain improved dramatically, she denied any further postprandial digestive difficulties and she was discharged home tolerating a regular diet. Her post-operative duplex ultrasound showed resolution of the velocity increase (down to 120 cm/s) and improved caliber of the celiac origin. However, her characteristic post-prandial abdominal pain returned about 1 month later. Although she had been able to gain several pounds of weight and eat despite the symptoms over the course of the first 2 weeks after discharge, she began losing weight again. A repeat duplex ultrasound now revealed an increase in her celiac artery velocity to 253 cm/s. Because of this, the decision was made to proceed with celiac artery angiography and stenting. Angiography showed residual narrowing and delayed filling of the celiac artery (Fig. 3a). A balloon-expandable stent was placed O. P. Palmer M. Tedesco K. Casey J. T. Lee G. A. Poultsides (&) Divisions of General and Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA e-mail: gpoultsides@stanford.edu